Purpose: The incomplete phenotypic penetrance of high iron Fe genotypes in relation to hemochromatosis poses a practical problem in the interpretation of the genotyping results by clinicians. We carried out meta-analyses of the associations between hemochromatosis genotypes C282Y/C282Y, C282Y/H63D, C282Y/wild-type, H63D/H63D, H63D/wild-type, versus wild-type/wild-type and iron overload, both provisional (elevated serum iron markers) and documented (elevated serum iron markers associated with evidence of iron excess based on liver biopsy and/or quantitative phlebotomy).
Methods: After reviewing 3572 article titles and evaluating 92 articles in detail, odds ratios were pooled from 43 study populations (9986 cases and 25,492 controls) using a random-effects model.
Results: Homozygosity for either variant or compound heterozygosity was associated with both provisional and documented iron overload. Single heterozygosity conferred no risk for elevated hepatic iron index and/or mobilizable iron by quantitative phlebotomy. In patients with clinical hereditary hemochromatosis, no evidence of provisional and documented iron overload with transferrin saturation (TS) values greater than 55% was evidenced for C282Y and H63D single heterozygotes whereas documented iron overload including TS of 45% to 50% was weakly associated with C282Y/wild-type genotype; H63D/H63D genotype was not associated with documented iron overload in patients with TS values of 45% to 50%.
Conclusions: The results, mainly from case-control studies, cannot necessarily be extrapolated to the general population.
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